1. Presented by Martin H. Cohen, M.D. at the 27 July 2004 meeting of the Oncologic Drugs Advisory Committee

2. NDA 21-677 Alimta® Pemetrexed LY231514

3. Proposed Indication Alimta as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy

4. Study Design One randomized trial comparing treatment with Alimta to treatment with docetaxel 75 mg/2 Stratification factors: P.S.; Disease stage; Number of prior regimens; Response to last prior chemo; prior platinum; prior paclitaxel; baseline homocysteine; treatment site

5. Docetaxel 2 nd line Survival PtsRRMed (mo) p OS 1 yr (%) p 1 yr DOC 75 vs BSC 55 49 5.5% -- 7.5 4.6 0.0137 12 <0.05 Doc 75 Vs IC (V/I) 125 123 5.7 0.8 5.7 5.6 0.1330 20 0.025

6. Alimta Administration Alimta 500 mg/m2 IV infusion over 10 minutes on Day 1 of each 21-day cycle. Folic acid 350-1000 mcg daily Vitamin B12 1000 mcg every 3 rd cycle Dexamethasone 4mg po bid days -1, 0, +1 (rash prophylaxis)

7. Docetaxel Administration Docetaxel 75 mg/m2 as an intravenous infusion over 60 minutes on Day 1 of each 21-day cycle. Dexamethasone 8 mg po bid days -1, 0, +1 (fluid retention & hypersensitivity)

8. Study Conduct 135 Investigational sites in 23 countries Approximately 21% of the study population came from United States Institutions

9. Selected Patient Characteristics Alimta N=283 Docetaxel N=288 PS 0-189%88% 1 Prior chemo regimen94%95% Prior platinum91%93% Prior paclitaxel27%26% Homocysteine > 1230%29%

10. Efficacy Endpoints Primary – Overall Survival Secondary – Response Rate and Duration – Time to Progression – Progression Free Survival – Symptom Burden (LCSS)

11. Response Rate & Duration Alimta N=264 Docetaxel N=274 CR (%) 1 (0.4)0 PR (%)23 (8.7)24 (8.8) Total RR9.1%8.8% 95% CI5.9, 13.25.7,12.8 Resp Dur (median)4.6 mo5.3 mo

12. Time to Progression ITTRT Alimta N=283 Doc N=288 Alimta n=265 Doc N=276 Median (mo)3.43.1 3.5 % censored25282025

13. Post-study chemotherapy Alimta N=265 Docetaxel N=276 Any drug126 (48%)107 (39%) Docetaxel85 (32%)11 (4%) Gemcitabine17 (6%)32 (12%) Vinorelbine6 (2%)25 (9%) Gefitinib5 (2%)21 (8%)

14. Post-study chemotherapy & Survival Alimta N=265 Docetaxel N=276 NMSN No P-S chemotherapy1396.2 mo1695.0 mo Post-study docetaxel859.6 mo1110.1 mo Other chemotherapy4110.6 mo9611.2 mo

15. No post-study chemo. Last PS Last PS Alimta N=139 Docetaxel N=169 0 or 1108 (78%)123 (73%) 228 (20%)37 (22%) 3 or 41 (1%)7 (4%) Unknown2 (1%)

16. Post-study chemotherapy & Survival Alimta N=265 Docetaxel N=276 NMSN No P-S chemotherapy1396.2 mo1695.0 mo Post-study docetaxel859.6 mo1110.1 mo Other chemotherapy4110.6 mo9611.2 mo

17. Patient Exposure Alimta N=265 Docetaxel N=276 Median No. of cycles44 % of planned dose intensity 96.694.4

18. All Toxicities Regardless of Causality Percent of Patients ToxicityAlimta N=265 Docetaxel N=276 p-value Grade 197.494.60.128 Grade 296.696.71.0 Grade 366.476.80.008 Grade 418.149.20.000 Grade 3 or 469.084.10.000

19. CTC Grade 3 or 4 Neutropenia* Alimta N=265 Docetaxel N=276 Febrile neutropenia*5 (2)35 (13) Infection with neutropenia0 (0)16 (5.8) * Uncorrected p value <0.001

20. All Toxicities Regardless of Causality Excluding WBC Events* ToxicityAlimta N=265 Docetaxel N=276 p-value Grade 195.592.0 0.112 Grade 295.195.3 >0.999 Grade 363.865.20.788 Grade 416.621.70.156 Grade 3 or 467.969.20.781 * febrile neutropenia, leukocytes, lymphopenia, neutrophils/ granulocytes, infection with grade 3 or 4 neutropenia, infection/febrile neutropenia, other

21. CTC Grade 3 or 4 AE’s Alimta (%)Docetaxel (%)p-value Alopecia0.43.00.04 Diarrhea0.44.00.01 Fatigue15.816.70.817 Nausea3.82.50.466 Vomiting1.51.41.0 Stomatitis1.1 1.0 Pulmonary6.89.80.217 Neurosensory*7.59.80.365 * Grade 2-4

22. Selected TEAEs – All grades* AlimtaDocetaxel Nausea98 (37%)59 (21%) Weight loss76 (29)44 (16) ALT increased23 (9)6 (2) AST increase20 (8)3 (1) Ccr decreased12 (5)1 (0.4) Alopecia19 (7)108 (39) * Selection based on an uncorrected p value < 0.001

23. Selected TEAEs –All Grades* AlimtaDocetaxel Myalgias23 (9)42 (15) Arthralgias19(7)36 (13) Neurotoxicity2 (1)10 (4) Diarrhea60 (23)91 (33) Constipation58 (22)34 (12) Fatigue133 (50)115 (42) Rash37 (14)19 (7) * Selection based on an uncorrected p value <0.05

24. Hospitalizations Alimta N=265 Docetaxel N=276 Admissions337364 Days17221410

25. Efficacy Conclusions Post-study chemotherapy confounds survival results - 85 (32%) of Alimta pts received post-study docetaxel - Patients who did not receive post-study chemotherapy had shorter survival - 30 more docetaxel treated patients received no post-study chemotherapy compared to Alimta treated patients. - Majority of untreated P-S patients had PS 0-1 Response rates were 9.1% (A) and 8.8% (D)

26. Safety Conclusions Toxicity spectrum of Docetaxel and Alimta differ. - Docetaxel produces more neutropenia and neutropenic complications (febrile neutropenia, infections, G-CSF use) neurotoxicity, myalgias, alopecia and diarrhea - Alimta produces more thrombocytopenia, skin rash, fatigue, nausea and vomiting, ALT and AST increase, decreased CCr, and weight loss. Folic acid and Vitamin B12 supplements are known to decrease Alimta toxicity. Whether they would also decrease docetaxel toxicity is unknown.